Understanding How Broadly Neutralizing Antibodies Evolve

As they mature, some antibodies accumulate mutations that make them better at binding to and neutralizing HIV

Antibodies are one of the main ways the body defends itself against invading pathogens. These infection-fighting proteins can bind to viruses and inactivate them. Antibodies are also thought to be essential to the protection afforded by most, if not all, existing vaccines.

In recent months, researchers have isolated several antibodies from the blood of HIV-infected individuals that are able to inactivate or neutralize a high percentage of HIV strains in laboratory tests (see VAX March 2010 Primer onUnderstanding Advances in the Search for Antibodies Against HIV). These antibodies are referred to as broadly neutralizing antibodies. Some of these antibodies can even neutralize HIV at very low concentrations, suggesting they are quite potent.

The goal now for AIDS vaccine researchers is to try to design vaccine candidates that can coax the body’s immune system to make similar potent, broadly neutralizing antibodies against HIV. Although this is a daunting task, researchers are making considerable progress in understanding how these broadly neutralizing antibodies evolve in HIV-infected individuals.

Antibody formation

There are many components of the immune system that play a role in fending off viruses. Antibodies are made by a type of immune cell produced in the bone marrow that are referred to as B cells. Millions of different versions of B cells exist. These B cells become activated when they come in contact with foreign pathogens, such as HIV. This triggers the B cell to become a plasma cell that is able to produce antibodies that are specific to HIV. Although many HIV-specific antibodies are produced, not all of them are capable of binding to HIV and neutralizing it (see VAX February 2007 Primer on Understanding Neutralizing Antibodies).

Once B cells bind to HIV, they start to multiply. As they multiply, the B cells begin to mutate or change their genes. Some of these genetic mutations in the B cells result in the production of antibodies that are better able to bind to HIV. These superior B cells then multiply again and again, triggering additional mutations. With each cycle of mutation and differentiation, the resulting antibodies are said to become more mature. The more mature the antibodies become, the better they are. This process is referred to as affinity maturation.

After researchers isolated the most recent broadly neutralizing antibodies against HIV, they began studying the characteristics of these antibodies and they found that they had gone through the process of affinity maturation many times, which is to say that they had accumulated many mutations. Studies have shown that all of the HIV-specific antibodies identified so far are highly affinity matured. In fact, these antibodies have accumulated many more mutations than other antibodies that have been studied.

Researchers do not yet know if all of these mutations are necessary for these antibodies to neutralize many different strains of HIV so well. But in some cases, studies have shown that reversing most of the mutations resulted in an antibody that could not neutralize HIV, suggesting at least some of the mutations are required.

Implications for vaccines?

To further study how broadly neutralizing antibodies evolve in HIV-infected individuals, researchers are going back to one of the original donors from whom some of the recent broadly neutralizing antibodies were isolated to isolate many other antibodies from their blood samples. This way they can identify and study the precursors to the broadly neutralizing antibodies and determine the path of evolution those antibodies had taken, much like constructing a family tree. This information will likely be useful to researchers as they try to develop vaccine candidates that can induce similar broadly neutralizing antibodies.